The era of plasticity began with the publication of a manuscript entitled “Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo” by Bjornson and colleagues (1). They pursued a hypothesis based on observations made by Valtz et al. who showed the ability of a single neuroectodermal cell (from rat cerebellar cell line ST15A) to form neuronal, glial, and muscle cells (2). A deluge of plasticity papers has since followed.
Initially, there were reports of cells from muscle giving rise to hematopoiesis (3) and then a variety of reports of marrow-derived cells giving rise to muscle (4-6), hepatocytes (7-9) and cardiac myocytes (10, 11). This suggested that hierarchical plasticity is the rule and that the local microenvironment determines the choice of differentiation pathways.
While most of these studies have been done with whole cell populations, several experimental designs have used highly purified hematopoietic marrow stem cells, showing that hepatocytes and myocardial myocytes could arise from these cells. However, even in this instance, the results did not address the question of whether the repopulating cells were cells with both hematopoietic and nonhematopoietic potential or whether there coexisted separate lineage-defined stem cells in the purified population experimentally obtained. Work from Verfaille and colleagues provides support for the concept of multiple stem cell types residing in the marrow. In their in vitro studies, they found a class of stem cells which can give rise to neural, mesenchymal, muscle and fat cells, but not to hematopoietic lineages. The question of origin can only be answered with clonal population studies. One such study, using limiting dilution techniques, has been reported and indicates clonal origin of many nonhematopoietic cell types from purified marrow hematopoietic stem cells (12).
Another unresolved issue is whether the hematopoietic potential demonstrated in nonhematopoietic tissue arose from nonhematopoietic tissue stem cells or hematopoietic stem cells, which coexisted in the nonhematopoietic tissue. The initial reports of muscle cells generating hematopoiesis implied that muscle stem cells were responsible. However, recent work from Kawada and Ogawa (13) indicates that these initial reports simply demonstrate the existence of hematopoietic stem cells, which are known to circulate in the blood, within the muscle tissue. That study demonstrates that following reconstitution of irradiated mice with genetically marked bone marrow cells, the cells from the muscle tissue that had reconstituted hematopoietic progeny were all of donor origin.
In vivo observations of stem cell plasticity have been extended to human cells. Almeida-Porada and coworkers (14), using a permissive, pre-immune fetal sheep engraftment model, have shown that non-purified fetal human brain cells (“neurosphere” cells) can give rise to hematopoietic, hepatic, renal and gut cells. These data clearly indicate that different tissues harbor cells with lineage potential for many other tissues, and that marrow is a particularly abundant source for these cells. They further indicate the overriding importance of specific microenvironments and their associated differentiation cues. Unfortunately, they do not as yet establish whether true hierarchical plasticity exists or whether multiple stem cells coexist in various tissues.
This model, of course, may hold for many other tissues, regardless of whether there are single or multiple stem cell types. When stem cells emigrate or are injected into a tissue, differentiation would be determined by the local environment. Thus, cardiac tissue might harbor, at least transiently, all stem cell types, but only cardiac-type stem cells would differentiate and make heart cells. Alternatively, one stem cell with open potential may be involved and its differentiation fate would then be determined by inductive signals delivered by the local environment.
There is another intriguing possibility, which is that the marrow could actually be the feeder tissue for all other local stem cell populations. In this scenario, marrow stem cells with general potential are continuously circulating and these circulating cells would be the source of local stem cells in the gut, skin, liver or brain. Thus, the marrow would be the ultimate source of all stem cells and would feed the tissue stem cells. This would still be consistent with there being one marrow stem cell with total plastic potential or many individual stem cells with specific lineage potentials.
Notwithstanding the mechanisms of stem cell biology being studied, there exists a need for technology permitting the delivery and affixing of stem cells to particular target tissues. At present, however, such technology has not been adequately developed.